Inhalation devices are devices capable of delivering aerosols to the body via the lungs. An aerosol is a dispersion of small solid particles or fine liquid droplets in a continuous gas phase. Aerosols of liquid formulations containing a bioactive agent or drug are required for numerous medical applications, such as the inhalative treatment of asthma, cystic fibrosis (CF), and a number of other respiratory diseases. Alternatively, inhalation devices may also be used for the inhalative administration of prophylactic or diagnostic formulations. The inhalation can either be through the mouth (oral inhalation) or through the nose (nasal inhalation); both routes requiring specifically shaped patient interfaces, such as mouthpieces, to reduce aerosol losses to ambient air. More common, especially when targeting the central and/or peripheral airways of the lungs, is oral inhalation.
In some cases, it is desired that the administered aerosol reaches even the smallest branches of the peripheral lungs, such as bronchioles and alveoli to ensure optimal absorption. In order to achieve the desired homogeneous droplet distribution in the gas phase, liquid formulations are typically atomized by the inhalation device. In some cases, the formed droplets may solidify to minute powder particles upon evaporation of the liquid carrier, once the aerosol cloud is expelled from the inhalation device.
Typical inhalation devices include dry powder inhalers (DPI), pressurized metered dose inhalers (pMDI), soft mist inhalers or Rayleigh spray inhalers (such as Respimat® inhaler, Medspray®) and nebulizers (such as ultrasonic nebulizers, jet nebulizers or vibrating mesh nebulizers).
Nebulizes are inhalation devices capable of converting a liquid into an inhalable aerosol in a continuous manner using a nebulizing means (or atomizing means, or aerosol generator), for example a piezo-electrically driven vibrating mesh assembly. Unlike DPIs, pMDIs and soft mist inhalers, which emit metered aerosols only upon actuation and within a very short time frame of few milliseconds, nebulizers operate continuously over the course of a few breaths up to about 45 min (or even longer if the patient requires breaks during an inhalation treatment). During this time, they emit aerosol either constantly or in pulses which are adapted to the user's breathing pattern; e.g., triggered by the onset of inhalation. The duration of the aerosol pulse may also be adapted to the patient's breathing pattern and/or lung function parameters. Nebulizers further differ from the afore mentioned inhalation devices (DPIs, pMDIs and soft mist inhalers) in that they do not per se emit metered amounts of aerosols, because they operate continuously, unless switched off, until the reservoir for the liquid formulation is empty.
An option for dosing the amount of medicine to be inhaled is the use of pre-filled single-use cartridges which are emptied completely into the inhalation device and subsequently nebulized in entirety. While being a favorable approach with regard to dosing reproducibility and hygiene, the dosing flexibility of such pre-filled single-use cartridges is limited.
In cases when the prescribed amount of medicine to be inhaled does not match the volume of the liquid formulation supplied in the container, it would be desirable that the nebulizer is capable of ensuring that only the prescribed amount of liquid is delivered in aerosol form.
A dosing system for such purpose is shown in EP 1 465 692 B1 which discloses a nebulizer including nebulization device and a reservoir which has a metering chamber and a second chamber. The metering chamber defines the volume of the substance to be nebulized and is arranged so as to feed said volume to the nebulization device, while any substance poured into the metering chamber in excess of its volume is received and retained in the second chamber. In other words, the metering chamber is filled until the liquid overflows into the second chamber, and only the metered volume inside the metering chamber is subsequently nebulized. This approach, as depicted as prior art in FIG. 1, is also not very flexible. In addition, dosing reproducibility may be negatively affected e.g. if the user does not keep the device in a horizontal orientation during filling or use. Moreover, any changes in the prescribed dose would require substantial modification of the device and a complete replacement of the metering chamber assembly. Furthermore, the metering system is not suitable for metering very small amounts of liquids which are substantially affected by adhesive and cohesive forces and do not easily flow from one chamber to another.
GB 2 272 389 A discloses another dosing system which is equipped with a manually actuated, syringe-type metering pump comprising a cylinder of defined inner volume and a movable piston. Upon withdrawal of the piston, liquid from a larger liquid supply tank is filled into the cylinder via an inlet valve. When pushing the piston into the cylinder, a droplet of liquid (e.g. 20 μL) is expelled via an outlet valve. An actual metering step occurs only with complete in/out strokes of the piston, making the system inflexible to the dosed volume. Further, due to the manual operation mode the system may fail to provide dosing accuracy and reproducibility.
Further dosing systems are disclosed in EP 1 205 199 A1 and US 2012/0216800 A1. The dosing system shown in both documents comprises a cylindrical filling chamber with a wider top portion and a narrower bottom portion which at its bottom end is closed by a valve. A plunger is inserted into the filling chamber from its wider top end along the chamtier's longitudinal axis. Once the plunger reaches the narrower bottom portion, a seal between plunger and the inner walls of the bottom portion is formed, so that liquid cannot be displaced towards the wider top end anymore. Thus upon continued insertion of the plunger, a metered amount of liquid is pushed out of the filling chamber's bottom portion through the valve, while the excess liquid remains in the filling chamber above the seal. When the plunger is retracted from the bottom portion, this excess liquid can flow into the bottom portion and can also be pushed out through the valve when the plunger is inserted once or several times more.
This can be advantageous in cases, where the filling chamber is deliberately filled with a multi-dose amount of liquid and the dosing system is supposed to be actuated repeatedly. However, it is highly undesirable in cases where such re-dosing is unintended and/or may even be harmful due to overdosing; e.g. when only specific fractions of typically marketed volumes are supposed to be administered to neonates, infants, children or to subjects with an improving health-condition. For instance, a nebulizer solution may only be available in ampoules containing 1 mL or more, while the subject should receive only 200 μL. The above described dosing systems would either allow the unintended administration of an extra 800 μL to a subject, or they would not nebulize all of the intended 200 μL due to adhesion- and cohesion induced losses in the metering chamber.
It is thus the aim of the invention to provide a dosing system for an inhalation device which overcomes any of the limitations of the prior art; e.g. by allowing for a higher dosing flexibility, reducing dosing deviations by minor handling errors and/or considerably decrease the risk of unintentional re-dosing. Another object is to provide a dosing system which is easy for the user to assemble and/or use and which has limited (losable) components. A further object is to provide a dosing system with high dosing accuracy even for small volumes.